- Email: [email protected]
Phospholipase A2 inhibitors in atherosclerosis: the race is on
Comment
previous drug treatments have already failed, and patients have substantial adverse effects.4 Still, about 40% of patients in Bussel and colleagues’ study were on concomitant standard therapy (usually steroids). Thus, a mutually enhancing effect cannot be ruled out. Second, it was previously assumed that thrombopoiesis is already turned on to compensate for increased platelet sequestration in adults with ITP. Today’s report clearly shows that eltrombopag can further enhance platelet production, which supports the idea of impaired thrombopoiesis in adults with ITP. These findings shed new light on pathological mechanisms in this condition.6 Romiplostim, which has also been shown by Bussel’s group to increase the platelet count in patients with ITP,7 is a thrombopoietin (TPO) peptide mimetic that activates the TPO-receptor similar to endogenous TPO.8 Eltrombopag, however, is a non-peptide small molecule, that binds to the TPO receptor at a distance from the binding site for TPO and seems to initiate signal transduction by a mechanism different from TPO. It is, therefore, not surprising that the effect of eltrombopag is additive to the effect of rhTPO in cell-based assays.8 The effectiveness and safety of romiplostim and eltrombopag have been documented when administered only for a relatively short time of weeks to months—ie, short in comparison with the duration of the disease, which can last for years or for life. Eltrombopag will probably add to the treatments for bridging certain situations of increased risk of bleeding in adults with ITP, mainly if corticosteroids are contraindicated or for non-responders to first-line treatment.9 It has therefore been licensed by the US Food and Drug Administration recently for the treatment
of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy, and whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. The role of eltrombopag in longterm treatment, and in deferring splenectomy, will be determined by its price and especially by its safety in long-term observational studies. *Simon Panzer, Ingrid Pabinger Department of Blood Group Serology and Transfusion Medicine, Division of Blood Group Serology (SP); Clinical Division of Haematology and Haemostaseology, Department of Medicine I (IP), Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria [email protected] We declare that we have no conflict of interest. 1
2
3
4 5
6 7
8 9
Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373: 641–48. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88: 3–40. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; 97: 2549–54. George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost 2006; 4: 1664–72. Sailer T, Lechner K, Panzer S, Kyrle PA, Pabinger I. The course of severe autoimmune thrombocytopenia in patients not undergoing splenectomy. Haematologica 2006; 91: 1041–45. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346: 995–1008. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371: 395–403. Kuter DJ. New thrombopoietic growth factors. Blood 2007; 109: 4607–16. Stasi R, Evangelista ML, Amadori S. Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura. Drugs 2008; 68: 901–12.
Phospholipase A2 inhibitors in atherosclerosis: the race is on See Articles page 649
608
Human A2 phospholipases (PLA2s) propagate inflammation by producing arachidonic acid precursors from membrane glycerophospholipids, which suggests this enzyme system as a promising drug target. Of the five major PLA2 classes,1 two have been implicated in the progression of atherosclerosis and its complications: secretory type and lipoprotein-associated. Population studies validate the independent predictive value of increased circulating secretory PLA2 (sPLA2) and lipoprotein-associated PLA2 for future cardiovascular
disease events.2,3 Furthermore, mechanistic studies in animals4,5 and human beings6,7 have shown that PLA2s are not only risk markers for cardiovascular disease events, but also aetiological risk factors for plaque progression, destabilisation, and rupture. Three sPLA2 subtypes participate in remodelling of lipoproteins, with adverse consequences for their function. sPLA2-X and sPLA2-V modify HDL, resulting in attenuation of its ability to mediate reverse-cholesterol transport. sPLA2-IIa and sPLA2-V remove phospholipids www.thelancet.com Vol 373 February 21, 2009
from LDL, rendering it more susceptible to retention via binding to matrix proteoglycans in the subintimal space.8 In this environment, LDL is subject to enhanced oxidation, further increasing its affinity as a substrate for lipoprotein-associated PLA2. The products of lipoprotein-associated PLA2 hydrolysis of oxidised LDL, lysophosphatidylcholine and oxidised free fatty acids, have multiple proatherogenic actions, the most important being to increase apoptosis of macrophages in the necrotic core of vulnerable plaques,7 which predisposes the individual to rupture and coronary or cerebral thrombosis. In The Lancet today, Robert Rosenson and colleagues report the findings of PLASMA, a phase II clinical trial in patients with stable coronary heart disease who received A-002 (1-H-indole-3-glyoxamide), an oral inhibitor of secretory PLA2s (sPLA2-IIa>sPLA2-X>sPLA2-V) or placebo.9 After 8 weeks of A-002 treatment, serum sPLA2 concentration progressively decreased to nearly an order of magnitude less than baseline; measures of vascular (oxidised LDL concentrations) and general (C-reactive protein) inflammation were reduced; and complex quantitative and qualitative lipoprotein changes were observed. Many of these changes were highly significant compared with placebo, and there was no excess of adverse events in the active treatment group. A-002 reduced LDL cholesterol concentration and particle numbers, mainly by reducing small dense LDL particles. Nearly two-thirds of study participants were taking statins and had lower baseline LDL cholesterol concentrations than did participants who were not on a statin, yet this group had disproportionate lowering of LDL cholesterol, by nearly 10%. These findings suggest that the anti-inflammatory effects of A-002 could be mediated in part via enhancement of LDL clearance by the LDL receptor. To further explore whether these favourable statin– A-002 interactions could translate into benefits in higher-risk coronary heart disease, 500 patients with acute coronary syndrome are currently being randomised within 96 h of diagnosis to the drug or placebo, on a background of high-dose atorvastatin, in the FRANCIS-ACS trial.10 After treatment for 24 weeks, the reduction of biomarkers and major adverse cardiac events will be compared. Meanwhile, an alternative PLA2 inhibitor that targets lipoprotein-associated PLA2, darapladib, was recently www.thelancet.com Vol 373 February 21, 2009
Brian J Bahnson
Comment
Figure: Ribbon model of lipoprotein-associated phospholipase A2
studied in 959 patients with stable coronary heart disease.11 Over 12 weeks, darapladib dose-dependently reduced circulating lipoprotein-associated PLA2 activity by 66% at maximum dose in patients receiving atorvastatin, and reduced other measures of inflammation such as C-reactive protein and interleukin 6. By contrast with the findings of PLASMA, darapladib did not lower LDL cholesterol in this trial, nor in another 12-month study of 330 patients with stable coronary heart disease who were treated intensively with antiplatelet agents, renin–angiotensin system antagonists, β blockers, and statins.12 Although in the 12-month study lipoprotein-associated PLA2 activity was decreased by 59% relative to placebo in darapladib-treated patients, C-reactive protein did not change and there was no difference in coronary total atheroma volume, measured by serial intravascular ultrasound. However, an increase in estimated necrotic core volume in placebo-treated patients was not seen in darapladib-treated patients; this structural modification of plaque is associated with a less rupture-prone phenotype. An intervention trial with darapladib, powered to assess its efficacy for cardiovascular disease event reduction, STABILITY, is being planned.13 PLA2s may be uniquely situated at the interface of lipoproteins and macrophages, promoting plaque 609
Comment
instability and clinical events by stimulating cell necrosis and apoptosis. These enzymes are therefore enticing targets for therapeutic inhibition. Two type-specific inhibitors in early phase clinical development show promising reduction of biomarkers and effects on surrogate endpoints, encouraging further investigation about whether they can reduce cardiovascular disease events without off-target toxicity. One signal of such toxicity has arisen with darapladib: an increase in blood pressure.12 It is also important to remember that recent attempts to develop selective anti-inflammatory (eg, cyclo-oxygenase 2 inhibitors) or antioxidant (eg, succinobuccol14) therapies initially showed favourable effects on biomarkers and measures of efficacy, but were subsequently found to be adverse or neutral for cardiovascular disease events, which suggests that challenges might lie ahead for PLA2 inhibitors. These difficulties could increase the regulatory hurdles that need to be cleared for these, or other, novel antiatherosclerotic therapies. Marshall A Corson Division of Cardiology, University of Washington/Harborview Medical Center, Seattle WA 98104, USA [email protected] I thank Brian J Bahnson, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA, for providing the figure. I have received speakers’ honoraria from Abbott, diaDexus, Forest, Merck-Schering Plough, Novartis, Oscient, and Sanofi-Aventis. 1
Schaloske RH, Dennis EA. The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta 2006; 1761: 1246–59.
2
3 4
5
6
7
8
9
10
11
12
13
14
Mallat Z, Benessiano J, Simon T, et al. Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-Norfolk study. Arterioscler Thromb Vasc Biol 2007; 27: 1177–83. Crandall MA, Corson MA. Use of biomarkers to develop treatment strategies for atherosclerosis. Curr Treat Options Cardiovasc Med 2008; 10: 304–15. Wilensky RL, Shi Y, Mohler ER, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008; 14: 1059–66. Menschikowski M, Hagelgans A, Siegert G. Secretory phospholipase A2 of group IIA: is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Prostaglandins Other Lipid Mediat 2006; 79: 1–33. Lavi S, McConnell JP, Rihal CS, et al. Local production of lipoproteinassociated phospholipase A2 and lysophosphatidylcholine in the coronary circulation: association with early coronary atherosclerosis and endothelial dysfunction in humans. Circulation 2007; 115: 2715–21. Kolodgie FD, Burke AP, Skorija KS, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26: 2523–29. Jonsson-Rylander AC, Lundin S, Rosengren B, Pettersson C, Hurt-Camejo E. Role of secretory phospholipases in atherogenesis. Curr Atheroscler Rep 2008; 10: 252–59. Rosenson RS, Hislop C, McConnell D, et al, for the PLASMA Investigators. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretary phospholipase A2 (PLASMA Study): a phase II double-blind, randomised, placebo-controlled trial. Lancet 2009; 373: 649–58. ClinicalTrials.gov. FRANCIS-ACS trial: a study of the safety and efficacy of A 002 in subjects with acute coronary syndromes. 2008. http:// clinicaltrials.gov/ct2/show/NCT00743925 (accessed Oct 20, 2008). Mohler ER, Ballantyne CM, Davidson MH, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2008; 51: 1632–41. Serruys PW, Garcia-Garcia HM, Buszman P, et al, on behalf of the Integrated Biomarker and Imaging study-2 Investigators. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118: 1172–82. ClinicalTrials.gov. The stabilization of atherosclerotic plaque by initiation of darapladib therapy trial (STABILITY). 2008. http://clinicaltrials.gov/ct2/ show/NCT00799903 (accessed Dec 15, 2008). Tardif JC, McMurray JJ, Klug E, et al, on behalf of the Aggressive Reduction of Inflammation Stops Events (ARISE) Trial Investigators. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 1761–68.
Cultural challenges and international research integrity International research collaborations have many benefits but also many barriers. The number of international collaborations, measured by the number of authors listed in publications, is growing exponentially.1 Recognition that researchers have limited opportunities to consider the effect of cultural issues led to the first international conference entitled Challenges and Tensions in International Research Collaborations,2 organised by the US Office of Research Integrity and the University of Minnesota in Minneapolis, USA on Oct 2–3, 2008. The ability to move back and forth through cultural, linguistic, institutional, and political boundaries is essential. Ways of handling data differ between nations, 610
and within research teams; negotiations on power and status can reflect different expectations of authorship or control over research design. Conventional working habits, including pacing, workloads, or sensitivity to deadlines and reporting requirements, can vary.3 Designing research can pose many difficulties, including whether concepts and words mean the same thing. In a study on chronic diseases aimed at developing a comparable quality-of-life measure, finding appropriate words for “cough” and “mucus” became central to the project’s success.4 There might be inconsistencies in the understanding of conditions such as stroke and Alzheimer’s disease in developing nations such as Uganda.5 Another planning concern is www.thelancet.com Vol 373 February 21, 2009
previous drug treatments have already failed, and patients have substantial adverse effects.4 Still, about 40% of patients in Bussel and colleagues’ study were on concomitant standard therapy (usually steroids). Thus, a mutually enhancing effect cannot be ruled out. Second, it was previously assumed that thrombopoiesis is already turned on to compensate for increased platelet sequestration in adults with ITP. Today’s report clearly shows that eltrombopag can further enhance platelet production, which supports the idea of impaired thrombopoiesis in adults with ITP. These findings shed new light on pathological mechanisms in this condition.6 Romiplostim, which has also been shown by Bussel’s group to increase the platelet count in patients with ITP,7 is a thrombopoietin (TPO) peptide mimetic that activates the TPO-receptor similar to endogenous TPO.8 Eltrombopag, however, is a non-peptide small molecule, that binds to the TPO receptor at a distance from the binding site for TPO and seems to initiate signal transduction by a mechanism different from TPO. It is, therefore, not surprising that the effect of eltrombopag is additive to the effect of rhTPO in cell-based assays.8 The effectiveness and safety of romiplostim and eltrombopag have been documented when administered only for a relatively short time of weeks to months—ie, short in comparison with the duration of the disease, which can last for years or for life. Eltrombopag will probably add to the treatments for bridging certain situations of increased risk of bleeding in adults with ITP, mainly if corticosteroids are contraindicated or for non-responders to first-line treatment.9 It has therefore been licensed by the US Food and Drug Administration recently for the treatment
of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy, and whose degree of thrombocytopenia and clinical condition increase the risk for bleeding. The role of eltrombopag in longterm treatment, and in deferring splenectomy, will be determined by its price and especially by its safety in long-term observational studies. *Simon Panzer, Ingrid Pabinger Department of Blood Group Serology and Transfusion Medicine, Division of Blood Group Serology (SP); Clinical Division of Haematology and Haemostaseology, Department of Medicine I (IP), Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria [email protected] We declare that we have no conflict of interest. 1
2
3
4 5
6 7
8 9
Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 2009; 373: 641–48. George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996; 88: 3–40. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001; 97: 2549–54. George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost 2006; 4: 1664–72. Sailer T, Lechner K, Panzer S, Kyrle PA, Pabinger I. The course of severe autoimmune thrombocytopenia in patients not undergoing splenectomy. Haematologica 2006; 91: 1041–45. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346: 995–1008. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008; 371: 395–403. Kuter DJ. New thrombopoietic growth factors. Blood 2007; 109: 4607–16. Stasi R, Evangelista ML, Amadori S. Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura. Drugs 2008; 68: 901–12.
Phospholipase A2 inhibitors in atherosclerosis: the race is on See Articles page 649
608
Human A2 phospholipases (PLA2s) propagate inflammation by producing arachidonic acid precursors from membrane glycerophospholipids, which suggests this enzyme system as a promising drug target. Of the five major PLA2 classes,1 two have been implicated in the progression of atherosclerosis and its complications: secretory type and lipoprotein-associated. Population studies validate the independent predictive value of increased circulating secretory PLA2 (sPLA2) and lipoprotein-associated PLA2 for future cardiovascular
disease events.2,3 Furthermore, mechanistic studies in animals4,5 and human beings6,7 have shown that PLA2s are not only risk markers for cardiovascular disease events, but also aetiological risk factors for plaque progression, destabilisation, and rupture. Three sPLA2 subtypes participate in remodelling of lipoproteins, with adverse consequences for their function. sPLA2-X and sPLA2-V modify HDL, resulting in attenuation of its ability to mediate reverse-cholesterol transport. sPLA2-IIa and sPLA2-V remove phospholipids www.thelancet.com Vol 373 February 21, 2009
from LDL, rendering it more susceptible to retention via binding to matrix proteoglycans in the subintimal space.8 In this environment, LDL is subject to enhanced oxidation, further increasing its affinity as a substrate for lipoprotein-associated PLA2. The products of lipoprotein-associated PLA2 hydrolysis of oxidised LDL, lysophosphatidylcholine and oxidised free fatty acids, have multiple proatherogenic actions, the most important being to increase apoptosis of macrophages in the necrotic core of vulnerable plaques,7 which predisposes the individual to rupture and coronary or cerebral thrombosis. In The Lancet today, Robert Rosenson and colleagues report the findings of PLASMA, a phase II clinical trial in patients with stable coronary heart disease who received A-002 (1-H-indole-3-glyoxamide), an oral inhibitor of secretory PLA2s (sPLA2-IIa>sPLA2-X>sPLA2-V) or placebo.9 After 8 weeks of A-002 treatment, serum sPLA2 concentration progressively decreased to nearly an order of magnitude less than baseline; measures of vascular (oxidised LDL concentrations) and general (C-reactive protein) inflammation were reduced; and complex quantitative and qualitative lipoprotein changes were observed. Many of these changes were highly significant compared with placebo, and there was no excess of adverse events in the active treatment group. A-002 reduced LDL cholesterol concentration and particle numbers, mainly by reducing small dense LDL particles. Nearly two-thirds of study participants were taking statins and had lower baseline LDL cholesterol concentrations than did participants who were not on a statin, yet this group had disproportionate lowering of LDL cholesterol, by nearly 10%. These findings suggest that the anti-inflammatory effects of A-002 could be mediated in part via enhancement of LDL clearance by the LDL receptor. To further explore whether these favourable statin– A-002 interactions could translate into benefits in higher-risk coronary heart disease, 500 patients with acute coronary syndrome are currently being randomised within 96 h of diagnosis to the drug or placebo, on a background of high-dose atorvastatin, in the FRANCIS-ACS trial.10 After treatment for 24 weeks, the reduction of biomarkers and major adverse cardiac events will be compared. Meanwhile, an alternative PLA2 inhibitor that targets lipoprotein-associated PLA2, darapladib, was recently www.thelancet.com Vol 373 February 21, 2009
Brian J Bahnson
Comment
Figure: Ribbon model of lipoprotein-associated phospholipase A2
studied in 959 patients with stable coronary heart disease.11 Over 12 weeks, darapladib dose-dependently reduced circulating lipoprotein-associated PLA2 activity by 66% at maximum dose in patients receiving atorvastatin, and reduced other measures of inflammation such as C-reactive protein and interleukin 6. By contrast with the findings of PLASMA, darapladib did not lower LDL cholesterol in this trial, nor in another 12-month study of 330 patients with stable coronary heart disease who were treated intensively with antiplatelet agents, renin–angiotensin system antagonists, β blockers, and statins.12 Although in the 12-month study lipoprotein-associated PLA2 activity was decreased by 59% relative to placebo in darapladib-treated patients, C-reactive protein did not change and there was no difference in coronary total atheroma volume, measured by serial intravascular ultrasound. However, an increase in estimated necrotic core volume in placebo-treated patients was not seen in darapladib-treated patients; this structural modification of plaque is associated with a less rupture-prone phenotype. An intervention trial with darapladib, powered to assess its efficacy for cardiovascular disease event reduction, STABILITY, is being planned.13 PLA2s may be uniquely situated at the interface of lipoproteins and macrophages, promoting plaque 609
Comment
instability and clinical events by stimulating cell necrosis and apoptosis. These enzymes are therefore enticing targets for therapeutic inhibition. Two type-specific inhibitors in early phase clinical development show promising reduction of biomarkers and effects on surrogate endpoints, encouraging further investigation about whether they can reduce cardiovascular disease events without off-target toxicity. One signal of such toxicity has arisen with darapladib: an increase in blood pressure.12 It is also important to remember that recent attempts to develop selective anti-inflammatory (eg, cyclo-oxygenase 2 inhibitors) or antioxidant (eg, succinobuccol14) therapies initially showed favourable effects on biomarkers and measures of efficacy, but were subsequently found to be adverse or neutral for cardiovascular disease events, which suggests that challenges might lie ahead for PLA2 inhibitors. These difficulties could increase the regulatory hurdles that need to be cleared for these, or other, novel antiatherosclerotic therapies. Marshall A Corson Division of Cardiology, University of Washington/Harborview Medical Center, Seattle WA 98104, USA [email protected] I thank Brian J Bahnson, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA, for providing the figure. I have received speakers’ honoraria from Abbott, diaDexus, Forest, Merck-Schering Plough, Novartis, Oscient, and Sanofi-Aventis. 1
Schaloske RH, Dennis EA. The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta 2006; 1761: 1246–59.
2
3 4
5
6
7
8
9
10
11
12
13
14
Mallat Z, Benessiano J, Simon T, et al. Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-Norfolk study. Arterioscler Thromb Vasc Biol 2007; 27: 1177–83. Crandall MA, Corson MA. Use of biomarkers to develop treatment strategies for atherosclerosis. Curr Treat Options Cardiovasc Med 2008; 10: 304–15. Wilensky RL, Shi Y, Mohler ER, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008; 14: 1059–66. Menschikowski M, Hagelgans A, Siegert G. Secretory phospholipase A2 of group IIA: is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Prostaglandins Other Lipid Mediat 2006; 79: 1–33. Lavi S, McConnell JP, Rihal CS, et al. Local production of lipoproteinassociated phospholipase A2 and lysophosphatidylcholine in the coronary circulation: association with early coronary atherosclerosis and endothelial dysfunction in humans. Circulation 2007; 115: 2715–21. Kolodgie FD, Burke AP, Skorija KS, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26: 2523–29. Jonsson-Rylander AC, Lundin S, Rosengren B, Pettersson C, Hurt-Camejo E. Role of secretory phospholipases in atherogenesis. Curr Atheroscler Rep 2008; 10: 252–59. Rosenson RS, Hislop C, McConnell D, et al, for the PLASMA Investigators. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretary phospholipase A2 (PLASMA Study): a phase II double-blind, randomised, placebo-controlled trial. Lancet 2009; 373: 649–58. ClinicalTrials.gov. FRANCIS-ACS trial: a study of the safety and efficacy of A 002 in subjects with acute coronary syndromes. 2008. http:// clinicaltrials.gov/ct2/show/NCT00743925 (accessed Oct 20, 2008). Mohler ER, Ballantyne CM, Davidson MH, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2008; 51: 1632–41. Serruys PW, Garcia-Garcia HM, Buszman P, et al, on behalf of the Integrated Biomarker and Imaging study-2 Investigators. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118: 1172–82. ClinicalTrials.gov. The stabilization of atherosclerotic plaque by initiation of darapladib therapy trial (STABILITY). 2008. http://clinicaltrials.gov/ct2/ show/NCT00799903 (accessed Dec 15, 2008). Tardif JC, McMurray JJ, Klug E, et al, on behalf of the Aggressive Reduction of Inflammation Stops Events (ARISE) Trial Investigators. Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 1761–68.
Cultural challenges and international research integrity International research collaborations have many benefits but also many barriers. The number of international collaborations, measured by the number of authors listed in publications, is growing exponentially.1 Recognition that researchers have limited opportunities to consider the effect of cultural issues led to the first international conference entitled Challenges and Tensions in International Research Collaborations,2 organised by the US Office of Research Integrity and the University of Minnesota in Minneapolis, USA on Oct 2–3, 2008. The ability to move back and forth through cultural, linguistic, institutional, and political boundaries is essential. Ways of handling data differ between nations, 610
and within research teams; negotiations on power and status can reflect different expectations of authorship or control over research design. Conventional working habits, including pacing, workloads, or sensitivity to deadlines and reporting requirements, can vary.3 Designing research can pose many difficulties, including whether concepts and words mean the same thing. In a study on chronic diseases aimed at developing a comparable quality-of-life measure, finding appropriate words for “cough” and “mucus” became central to the project’s success.4 There might be inconsistencies in the understanding of conditions such as stroke and Alzheimer’s disease in developing nations such as Uganda.5 Another planning concern is www.thelancet.com Vol 373 February 21, 2009